外泌体对上皮-间质转化调控作用的研究进展
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摘要
外泌体是一种具有生物活性的膜性囊泡,既可在细胞间传递活性物质,还可通过调控细胞间的信息传递参与细胞活动。上皮-间质转化(EMT)是上皮细胞获得间充质细胞特性的过程,在众多疾病中发挥了重要作用。研究表明,外泌体在EMT的发生发展过程中具有双向作用。一方面,外泌体可促进细胞发生EMT,赋予肿瘤细胞侵袭和转移能力,促进血管新生和加快肿瘤生长;另一方面,外泌体亦可抑制EMT,发挥减弱肿瘤细胞侵袭能力,抑制心、肝、肾纤维化,改善心肌梗死等作用。外泌体可能是通过携带EMT相关蛋白或miRNA,调控EMT相关信号通路发挥双向调节作用。
Exosome, a membranous vesicle with biological activity, not only transmits active substances between cells but also transfers information between cells to participate in cell communication. Epithelial-mesenchymal transition(EMT) is a process by which epithelial cells acquire migratory and invasive properties to become mesenchymal stem cells. EMT is essential for the development of a spectrum of diseases. Studies have shown that exosomes have dual effects on EMT to, on the one hand,promote EMT and tumor cell invasion and metastasis and accelerate angiogenesis and tumor growth; on the other hand,exosomes can suppress tumor cell invasion, inhibit fibrosis of the heart, liver and kidney, and improve myocardial infarction by inhibiting EMT. Exosomes modulate EMT-related signaling pathways by carrying EMT-related proteins or miRNA to exert their bi-directional regulatory effects.
Exosome, a membranous vesicle with biological activity, not only transmits active substances between cells but also transfers information between cells to participate in cell communication. Epithelial-mesenchymal transition(EMT) is a process by which epithelial cells acquire migratory and invasive properties to become mesenchymal stem cells. EMT is essential for the development of a spectrum of diseases. Studies have shown that exosomes have dual effects on EMT to, on the one hand,promote EMT and tumor cell invasion and metastasis and accelerate angiogenesis and tumor growth; on the other hand,exosomes can suppress tumor cell invasion, inhibit fibrosis of the heart, liver and kidney, and improve myocardial infarction by inhibiting EMT. Exosomes modulate EMT-related signaling pathways by carrying EMT-related proteins or miRNA to exert their bi-directional regulatory effects.
引文
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[11]Franzen CA, Blackwell RH, Todorovic V, et al. Urothelial cells undergo epithelial-to-mesenchymal transition after exposure to muscle invasive bladder cancer exosomes[J]. Oncogenesis, 2015, 4:e163.
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[13]Tsai JH, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis[J]. Genes Dev, 2013, 27(20):2192-206.
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[15]Davis FM, Stewart TA, Thompson EW, et al. Targeting EMT in cancer:opportunities for pharmacological intervention[J]. Trends Pharmacol Sci, 2014, 35(9):479-88.
[16]易红艳,周琛斐,梁莉,等.宫颈癌细胞分泌外泌体介导上皮-间质转化提高癌前细胞侵袭能力的体外研究[J].现代妇产科进展, 2017, 26(3):165-8.
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[18]Rahman MA, Barger JF, Lovat F, et al. Lung cancer exosomes as drivers of epithelial mesenchymal transition[J]. Oncotarget, 2016, 7(34):54852-66.
[19]Min H, Sun X, Yang X, et al. Exosomes derived from irradiated esophageal carcinoma-infiltrating T cells promote metastasis by inducing the epithelial-mesenchymal transition in esophageal cancer cells[J]. Pathol Oncol Res, 2018, 24(1):11-8.
[20]Aga M, Bentz GL, Raffa S, et al. Exosomal HIF1 alpha supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes[J]. Oncogene, 2014, 33(37):4613-22.
[21]Xiao D, Barry S, Kmetz D, et al. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment[J]. Cancer Lett, 2016, 376(2):318-27.
[22]Fujiwara T, Eguchi T, Sogawa C, et al. Carcinogenic epithelialmesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab[J]. Oral Oncol, 2018, 86:251-7.
[23]Hsieh CH, Tai SK, Yang MH. Snail-overexpressing cancer cells promote M2-Like polarization of tumor-associated macrophages by delivering miR-21-abundant exosomes[J]. Neoplasia, 2018, 20(8):775-88.
[24]Ota Y, Takahashi K, Otake S, et al. Extracellular vesicle-encapsulated miR-30e suppresses cholangiocarcinoma cell invasion and migration via inhibiting epithelial-mesenchymal transition[J].Oncotarget, 2018, 9(23):16400-17.
[25]Li YY, Tao YW, Gao S, et al. Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p[J]. EBiomedicine, 2018, 36:209-20.
[26]Li BL, Lu W, Qu JJ, et al. Loss of exosomal miR-148b from cancerassociated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis[J]. J Cell Physiol, 2019, 234(3):2943-53.
[27]李典,何大维,唐波,等.人脐带间充质干细胞外泌体抑制草酸及草酸钙诱导的HK-2细胞上皮间质转化[J].中国细胞生物学学报,2018, 40(6):913-20.
[28]俞静.人脐带间质干细胞外泌体对肾间质纤维化的修复及机制研究[D].镇江:江苏大学, 2017.
[29]俞静,张荣雪,贾浩源,等.脐带间质干细胞来源的外泌体抑制TGF-β1诱导的NRK-52E细胞上皮-间质转化[J].江苏大学学报:医学版,2017, 27(4):277-81.
[30]Li L, Huang LP, Sung S, et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury[J]. Kidney Int, 2008, 74(12):1526-37.
[31]Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis[J]. Stem Cells Dev, 2013, 22(6):845-54.
[32]Foglio E, Puddighinu G, Fasanaro PA, et al. Exosomal clusterin,identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis[J]. Int J Cardiol, 2015, 197:333-47.
[33]Beibei L, Juanjuan W, Lianbo S, et al. Mesenchymal stem cellderived exosome inhibits high hlucose-induced fibroblasts transdifferentiation via TGF-β1/Smad2/3 signaling pathway[J]. Chin J Cell Biol, 2017, 39(7):916-25.
[34]You YW, Shan Y, Chen J, et al. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis[J]. Cancer Sci, 2015, 106(12):1669-77.
[35]Jeppesen DK, Nawrocki A, Jensen SG, et al. Quantitative proteomics of fractionated membrane and lumen exosome proteins from isogenic metastatic and nonmetastatic bladder cancer cells reveal differential expression of EMT factors[J]. Proteomics, 2014, 14(6):699-712.
[36]Kruger S, Abd Elmageed ZY, Hawke DH, et al. Molecular characterization of exosome-like vesicles from breast cancer cells[J]. BMC Cancer, 2014, 14:44.
[37]Cha D J, Franklin J L, Dou Y, et al. KRAS-dependent sorting of miRNA to exosomes[J]. Elife, 2015, 4:e07197.
[38]Condorelli G, Elvira D, Danilo F, et al. Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer[J]. Cancer Res, 2017, 77(4):19592-608.
[39]刘金瑞.长期限食及模拟限食下调微囊泡中miR-21可延缓肾脏衰老相关纤维化的调控机制[D].长春:吉林大学, 2014.
[40]Diepenbruck M, Christofori G. Epithelial-mesenchymal transition(EMT)and metastasis:yes, no, maybe[J]? Curr Opin Cell Biol,2016, 43:7-13.
[41]Burger GA, Danen EHJ, Beltman JB. Deciphering epithelialmesenchymal transition regulatory networks in cancer through computational approaches[J]. Frontiers Oncol, 2017, 7:162.
[42]Ung TH, Madsen HJ, Hellwinkel JE, et al. Exosome proteomics reveals transcriptional regulator proteins with potential to mediate downstream pathways[J]. Cancer Sci, 2014, 105(11):1384-92.
[43]Chen L, Guo P, He YC, et al. HCC-derived exosomes elicit HCC progression and recurrence by epithelialmesenchymal transition through MAPK/ERK signalling pathway[J]. Cell Death Dis, 2018,9:513.
[44]Fu X, Liu MJ, Qu SY, et al. Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway[J]. J Exp Clin Cancer Res, 2018, 37:52.
[45]Hu HB, Xu ZL, Li C, et al. MiR-145 and miR-203 represses TGFbeta-induced epithelial-mesenchymal transition and invasion by inhibiting SMAD3 in non-small cell lung cancer cells[J]. Lung Cancer, 2016, 97:87-94.
[46]Fang S, Xu C, Zhang YT, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal MicroRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-beta/SMAD2 pathway during wound healing[J]. Stem Cells Transl Med,2016, 5(10):1425-39.
[2] Davis ME. Exosomes what do we love so much about them[J]? Circ Res, 2016, 119(12):1280-2.
[3] Lamparski HG, Metha-Damani A, Yao JY, et al. Production and characterization of clinical grade exosomes derived from dendritic cells[J]. J Immunol Methods, 2002, 270(2):211-26.
[4] Vlassov AV, Magdaleno S, Setterquist R, et al. Exosomes:current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials[J]. Biochim Biophys Acta, 2012, 1820(7):940-8.
[5] Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication[J]. Curr Opin Cell Biol, 2009, 21(4):575-81.
[6] Jia Y, Chen Y, Wang Q, et al. Exosome:emerging biomarker in breast cancer[J]. Oncotarget, 2017, 8(25):41717-33.
[7] Teng XM, Chen L, Chen WQ, et al. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation[J]. Cell Physiol Biochem, 2015, 37(6):2415-24.
[8] Mead B, Tomarev S. Bone marrow-derived mesenchymal stem cellsderived exosomes promote survival of retinal ganglion cells through miRNA-dependent mechanisms[J]. Stem Cells Transl Med, 2017, 6(4):1273-85.
[9] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition[J]. J Clin Invest, 2009, 119(6):1420-8.
[10]Vella LJ. The emerging role of exosomes in epithelial-mesenchymaltransition in cancer[J]. Front Oncol, 2014, 4:361.
[11]Franzen CA, Blackwell RH, Todorovic V, et al. Urothelial cells undergo epithelial-to-mesenchymal transition after exposure to muscle invasive bladder cancer exosomes[J]. Oncogenesis, 2015, 4:e163.
[12]Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelialmesenchymal transition[J]. Nat Rev Mol Cell Biol, 2014, 15(3):178-96.
[13]Tsai JH, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis[J]. Genes Dev, 2013, 27(20):2192-206.
[14]Felipe Lima J, Nofech-Mozes S, Bayani J, et al. EMT in breast carcinoma-A review[J]. J Clin Med, 2016, 5(7):65.
[15]Davis FM, Stewart TA, Thompson EW, et al. Targeting EMT in cancer:opportunities for pharmacological intervention[J]. Trends Pharmacol Sci, 2014, 35(9):479-88.
[16]易红艳,周琛斐,梁莉,等.宫颈癌细胞分泌外泌体介导上皮-间质转化提高癌前细胞侵袭能力的体外研究[J].现代妇产科进展, 2017, 26(3):165-8.
[17]Kim J, Kim TY, Lee MS, et al. Exosome cargo reflects TGF-beta 1-mediated epithelial-to-mesenchymal transition(EMT)status in A549 human lung adenocarcinoma cells[J]. Biochem Biophys Res Commun, 2016, 478(2):643-8.
[18]Rahman MA, Barger JF, Lovat F, et al. Lung cancer exosomes as drivers of epithelial mesenchymal transition[J]. Oncotarget, 2016, 7(34):54852-66.
[19]Min H, Sun X, Yang X, et al. Exosomes derived from irradiated esophageal carcinoma-infiltrating T cells promote metastasis by inducing the epithelial-mesenchymal transition in esophageal cancer cells[J]. Pathol Oncol Res, 2018, 24(1):11-8.
[20]Aga M, Bentz GL, Raffa S, et al. Exosomal HIF1 alpha supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes[J]. Oncogene, 2014, 33(37):4613-22.
[21]Xiao D, Barry S, Kmetz D, et al. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment[J]. Cancer Lett, 2016, 376(2):318-27.
[22]Fujiwara T, Eguchi T, Sogawa C, et al. Carcinogenic epithelialmesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab[J]. Oral Oncol, 2018, 86:251-7.
[23]Hsieh CH, Tai SK, Yang MH. Snail-overexpressing cancer cells promote M2-Like polarization of tumor-associated macrophages by delivering miR-21-abundant exosomes[J]. Neoplasia, 2018, 20(8):775-88.
[24]Ota Y, Takahashi K, Otake S, et al. Extracellular vesicle-encapsulated miR-30e suppresses cholangiocarcinoma cell invasion and migration via inhibiting epithelial-mesenchymal transition[J].Oncotarget, 2018, 9(23):16400-17.
[25]Li YY, Tao YW, Gao S, et al. Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p[J]. EBiomedicine, 2018, 36:209-20.
[26]Li BL, Lu W, Qu JJ, et al. Loss of exosomal miR-148b from cancerassociated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis[J]. J Cell Physiol, 2019, 234(3):2943-53.
[27]李典,何大维,唐波,等.人脐带间充质干细胞外泌体抑制草酸及草酸钙诱导的HK-2细胞上皮间质转化[J].中国细胞生物学学报,2018, 40(6):913-20.
[28]俞静.人脐带间质干细胞外泌体对肾间质纤维化的修复及机制研究[D].镇江:江苏大学, 2017.
[29]俞静,张荣雪,贾浩源,等.脐带间质干细胞来源的外泌体抑制TGF-β1诱导的NRK-52E细胞上皮-间质转化[J].江苏大学学报:医学版,2017, 27(4):277-81.
[30]Li L, Huang LP, Sung S, et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury[J]. Kidney Int, 2008, 74(12):1526-37.
[31]Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis[J]. Stem Cells Dev, 2013, 22(6):845-54.
[32]Foglio E, Puddighinu G, Fasanaro PA, et al. Exosomal clusterin,identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis[J]. Int J Cardiol, 2015, 197:333-47.
[33]Beibei L, Juanjuan W, Lianbo S, et al. Mesenchymal stem cellderived exosome inhibits high hlucose-induced fibroblasts transdifferentiation via TGF-β1/Smad2/3 signaling pathway[J]. Chin J Cell Biol, 2017, 39(7):916-25.
[34]You YW, Shan Y, Chen J, et al. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis[J]. Cancer Sci, 2015, 106(12):1669-77.
[35]Jeppesen DK, Nawrocki A, Jensen SG, et al. Quantitative proteomics of fractionated membrane and lumen exosome proteins from isogenic metastatic and nonmetastatic bladder cancer cells reveal differential expression of EMT factors[J]. Proteomics, 2014, 14(6):699-712.
[36]Kruger S, Abd Elmageed ZY, Hawke DH, et al. Molecular characterization of exosome-like vesicles from breast cancer cells[J]. BMC Cancer, 2014, 14:44.
[37]Cha D J, Franklin J L, Dou Y, et al. KRAS-dependent sorting of miRNA to exosomes[J]. Elife, 2015, 4:e07197.
[38]Condorelli G, Elvira D, Danilo F, et al. Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer[J]. Cancer Res, 2017, 77(4):19592-608.
[39]刘金瑞.长期限食及模拟限食下调微囊泡中miR-21可延缓肾脏衰老相关纤维化的调控机制[D].长春:吉林大学, 2014.
[40]Diepenbruck M, Christofori G. Epithelial-mesenchymal transition(EMT)and metastasis:yes, no, maybe[J]? Curr Opin Cell Biol,2016, 43:7-13.
[41]Burger GA, Danen EHJ, Beltman JB. Deciphering epithelialmesenchymal transition regulatory networks in cancer through computational approaches[J]. Frontiers Oncol, 2017, 7:162.
[42]Ung TH, Madsen HJ, Hellwinkel JE, et al. Exosome proteomics reveals transcriptional regulator proteins with potential to mediate downstream pathways[J]. Cancer Sci, 2014, 105(11):1384-92.
[43]Chen L, Guo P, He YC, et al. HCC-derived exosomes elicit HCC progression and recurrence by epithelialmesenchymal transition through MAPK/ERK signalling pathway[J]. Cell Death Dis, 2018,9:513.
[44]Fu X, Liu MJ, Qu SY, et al. Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway[J]. J Exp Clin Cancer Res, 2018, 37:52.
[45]Hu HB, Xu ZL, Li C, et al. MiR-145 and miR-203 represses TGFbeta-induced epithelial-mesenchymal transition and invasion by inhibiting SMAD3 in non-small cell lung cancer cells[J]. Lung Cancer, 2016, 97:87-94.
[46]Fang S, Xu C, Zhang YT, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal MicroRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-beta/SMAD2 pathway during wound healing[J]. Stem Cells Transl Med,2016, 5(10):1425-39.